Osteoclasts are active in bone forming metastases of prostate cancer patients

PLoS One. 2008;3(11):e3627. doi: 10.1371/journal.pone.0003627. Epub 2008 Nov 3.

Abstract

Background: Bone forming metastases are a common and disabling consequence of prostate cancer (CaP). The potential role of osteoclast activity in CaP bone metastases is not completely explained. In this study, we investigated ex vivo whether the osteolytic activity is present and how it is ruled in CaP patients with bone forming metastases.

Methodology: Forty-six patients affected by newly diagnosed CaP and healthy controls were enrolled. At diagnosis, 37 patients had a primary tumour only, while 9 had primary tumour and concomitant bone forming metastases. In all patients there was no evidence of metastasis to other non-bone sites. For all patients and controls we collected blood and urinary samples. We evaluated patients' bone homeostasis; we made peripheral blood mononuclear cell (PBMC) cultures to detect in vitro osteoclastogenesis; we dosed serum expression of molecules involved in cancer induced osteoclatogenesis, such as RANKL, OPG, TNF-alpha, DKK-1 and IL-7. By Real-Time PCR, we quantified DKK-1 and IL-7 gene expression on micro-dissected tumour and healthy tissue sections.

Principal findings: CaP bone metastatic patients showed bone metabolism disruption with increased bone resorption and formation compared to non-bone metastatic patients and healthy controls. The CaP PBMC cultures showed an enhanced osteoclastogenesis in bone metastatic patients, due to an increase of RANKL/OPG ratio. We detected increased DKK-1 serum levels and tissue gene expression in patients compared to controls. IL-7 resulted high in patients' sera, but its tissue gene expression was comparable in patients and controls.

Conclusions: We demonstrated ex vivo that osteoclastogenesis is an active mechanism in tumour nesting of bone forming metastatic cancer and that serum DKK-1 levels are increased in CaP patients, suggesting to deeply investigate its role as tumour marker.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Bone Neoplasms / blood
  • Bone Neoplasms / etiology*
  • Bone Neoplasms / physiopathology
  • Bone Neoplasms / secondary*
  • Bone Remodeling / genetics
  • Bone Remodeling / physiology
  • Bone Resorption / genetics
  • Bone Resorption / physiopathology
  • Carcinoma / blood
  • Carcinoma / genetics
  • Carcinoma / pathology*
  • Carcinoma / physiopathology
  • Case-Control Studies
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Cross-Sectional Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-7 / blood
  • Interleukin-7 / genetics
  • Male
  • Middle Aged
  • Osteoclasts / metabolism
  • Osteoclasts / physiology*
  • Osteoprotegerin / blood
  • Osteoprotegerin / genetics
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / physiopathology
  • RANK Ligand / blood
  • RANK Ligand / genetics

Substances

  • DKK1 protein, human
  • IL7 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-7
  • Osteoprotegerin
  • RANK Ligand
  • TNFRSF11B protein, human
  • TNFSF11 protein, human